Abstract
3519 Background: IGF1R is a tyrosine kinase receptor that mediates both mitogenic and antiapoptotic pathways and that is expressed in a variety of tumor types. IGF1R activation also mediates resistance to a broad range of cytotoxic and targeted agents. MK-0646 is a humanized IgG1 MAb that binds to IGF1R with a Kd <1 nM, competes with ligand-binding, prevents receptor activation and promotes receptor internalization. This first in man phase I trial with MK-0646 was designed to study its safety; to identify an optimal dose and schedule; and to seek for in vivo evidence of IGF1R signaling blockade in tumors. Methods: Pts with IGF1R-expressing tumors by IHC were allocated to dose escalating cohorts of at least 6 patients each of MK-0646 given IV qW (1.25, 2.5, 5.0, 10, 15 and 20 mg/kg). Sequential (baseline and day 14) skin and tumor biopsies were collected for PD analysis. FDG-PET was also performed prior and on-treatment. Results: 48 pts (23 m, 25 f, median age 59 yrs), with chemo-refractory solid tumors (13 colorectal, 11 breast, 5 Ewing’s and 19 other) have been entered to date and are evaluable for safety assessment. One dose limiting toxicity (G3 purpura) was noted at 5.0 mg/Kg. Grade I-II hyperglycemia responding to metformin occurred in 10% of pts. MTD has not been identified. Plasma IGF1 levels increased in all pts. PK data support dose proportionality with a mean terminal t1/2 of 95 hours, and clearance saturation and a mean Cmin over the target at doses >5 mg/Kg. For pts with evaluable paired tumor biopsies (n=13), decreases in IGF1R expression, inhibition of IGF1R signaling (decreases in pAKT, pMAPK and pS6) and a decrease in Ki67 was observed at doses >5 mg/kg. FDG-PET metabolic responses occurred in 3 pts. One pt. with Ewing’s showed a mixed radiological response. Three pts had stable disease for >3 months. Conclusions: MK-0646 is safe and tolerable, exhibits approximately dose-proportional PK, inhibits IGF1R signaling and proliferation in treated tumors and has clinical activity. PK findings support a more extended dose-interval that is currently being evaluated (q2W & q3W). Updated clinical and biomarker data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck Merck
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